Derivatives of p-aminoalkylphenylsulfonyl-2-imino-imidazolidines

ABSTRACT

COMPOUNDS OF THE CLASS OF SUBSTITUTED P-AMINOALKYLPHENYSULFONYL-2-IMINO-IMIDAZOLIDINES AND THE PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF HAVE HYPOGLYCEMIC ACTIVITY; THESE COMPOUNDS ARE ACTIVE INGREDIENTS OF PHARMACEUTICAL COMPOSITONS AND ARE USEFUL FOR THE TREATMENT OF DIABETES MELLOTUS; A TYPICAL EMBODIMENT IS 1 - (P - (2 - (ETHOXYCARBONYLAMINO)-ETHYL)-PHENYLSULFONYL-2-IMINO-3-CYCLOHEXYL -IMIDAZOLIDINE.

United States Patent Ofiice 3,708,494 Patented Jan. 2, 1973 US. Cl.260309.7 3 Claims ABSTRACT OF THE DISCLOSURE Compounds of the class ofsubstituted p-aminoalkylphenylsulfonyl-2-imino-imidazolidines and thepharmaceutically acceptable acid addition salts thereof havehypoglycemic activity; these compounds are active ingredients ofpharmaceutical compositions and are useful for the treatment of diabetesmellitus; a typical embodiment is 1 [p [2(ethoxycarbonylamino)-ethyl]-phenylsulfonyl]2-imino-3cyclohexyl-imidazolidine.

The present invention relates to derivatives ofp-aminoalkylphenylsulfony1-2-iminoimidazolidines, to pharmaceuticalcompositions containing these compounds and to their use.

More particularly, the present invention relates to compounds of formulawherein R is alkyl having from one to six carbon atoms, cycloalkyl orcycloalkenyl having from five to eight carbon atoms, or allyl;

R is hydrogen, methyl or ethyl;

R is alkyl having from one to six carbon atoms, cycloalkyl having atmost eight carbon atoms, allyl, phenyl or phenylalkyl having at mostnine carbon atoms;

In is the integer 2 or 3;

and the pharmaceutically acceptable acid addition salts thereof.

These compounds have been found to have a hypoglycemic eifect inwarm-blooded animals upon oral or parenteral administration. Thisactivity, in combination with a favourable therapeutic index,characterizes the compounds of the present invention as being suitablefor the treatment of diabetes mellitus.

The therapeutic action can be demonstrated in standard tests onexperimental animals.

In the compounds of Formula I, R as alkyl, can be e.g. the methyl,ethyl, propyl, isopropyl, butyl, sec.butyl, tert.butyl, isobutyl,pentyl, isopentyl, 2,2-dimethylpropyl, l-methylbutyl, l-ethylpropyl,1,2-dimethylpropyl, n-hexyl, methylpentyl, dimethylbutyl or ethylbutylgroup. As cycloalkyl, R, can be the cyclopentyl group which can beoptionally substituted by alkyl groups having one to three carbon atoms,the cyclohexyl group which can be substituted by ethyl or methyl, andthe cycloheptyl group optionally substituted by methyl, as well as thecyclooctyl group. As cycloalkenyl, R, can be the 2-cyclopenten-1-yl, the2-cyclohexen-l-yl, the 3-cyclohexen-1-yl, the Z-methyl-2-cyclohexen-1-yl, the 3-cyclohepten-1-yl group, or a cyclooctenylgroup.

The substituent R comprises the same alkyl and cycloalkyl groups whichwere mentioned for R as the phenylalkyl group, R can be the benzylgroup, the phenylethyl group or the a-methylphenylethyl group.

Using the process according to the invention, compounds of Formula I areproduced by reacting a compound of formula I IIH wherein R R and m havethe meaning given under Formula I,

with a compound of formula 0 R -O-ii-X (111) wherein R has the meaninggiven under Formula I, and X represents a halogen atom or an acyloxygroup derived from a monoester of carbonic acid,

and optionally converting the reaction products obtained into the saltof an inorganic or organic acid.

As compounds of Formula III, chloroand bromoformates are particularlysuitable in which R has the meaning given under Formula '1. Suitableacyloxy compounds of Formula III are pyrocarboru'c acid esters offormula 0 O (i-O-(l-OR,

wherein R has the meaning given under Formula I. These substances can,for example, be obtained by reacting chloroformates with alkali-metalsalts of monoesters of carbonic acid. Mixed pyrocarbonic acid estersmay, however, also be used. In this case one of the R radicalsrepresents a methyl or an ethyl group. W Thoma, H. Rinke [Liebigs Ann.Chem. 624, 30 (1959)].

The reaction is performed for example at temperatures between 20 and +20C. in an inert organic solvent. Suitable examples are: hydrocarbons suchas benzene, toluene or xylene, ethers such as diethylether, dioxane ortetrahydrofuran, chlorinated hydrocarbons such as methylene chloride,and lower ketones such as acetone or methyl ethyl ketone.

A chloroformate of Formula III is reacted according I to the inventionpreferably in the presence of an acidbinding agent. For this purposeinorganic bases or salts such as, for example, an alkali hydroxide,acetate, hydrogen carbonate, carbonate or phosphate such as sodiumhydroxide, acetate, hydrogen carbonate and phosphate, or thecorresponding potassium compounds may be used. In addition, calciumoxide, carbonate, and phosphate, and magnesium carbonate may also beused. Instead of inorganic bases or salts, organic bases such as, forexample, pyridine, trimethylor triethylamine, diisopropylamine, orcollidine are suitable. When these are used in excess they can also beused as solvent.

Instead of amines of the general Formula II, in the reaction accordingto the invention with a chloroformate, N-alkali metal derivatives ofthese compounds, e.g. sodium, potassium or lithium derivatives may alsobe employed.

The starting materials of the general Formula II are new compounds andcan be produced, e.g. by reacting a reactive derivative of a sulphonicacid of formula H (IV) wherein R represents a simple alkyl or arylradical, for example a methyl or a phenyl group, and m has the meaninggiven in Formula I,

with 2-amino-2-imidazoline derivatives of formula wherein R and R havethe meaning given under Formula I,

and then hydrolytically cleaving off the acyl protective grouping(RCO--). The N-acyl compounds derived from those of Formula II which areobtained as intermediates have likewise previously not been described inthe literature.

Suitable reactive derivatives of a sulphonic acid of Formula V arehalides, especially chlorides and anhydrides of formula 2 (IVa) whereinm has the meaning given under Formula I.

wherein m has the meaning given under Formula I,

with substituted N-(2-bromoalkyl)-cyanoamides in an alkaline medium.

The starting materials of Formula III are prepared by the commonly knownmethods for chloroformates.

The new substances of Formula I, or the pharmaceutically acceptable acidaddition salts thereof, can be administered orally or parenterally. Forsalt formation, it is possible to use physiologically suitable inorganicor organic acids such as, e.g. hydrochloric acid, hydrobromic acid,sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid,lactic acid, succinic acid, tartaric acid and maleic acid, but alsohypoglycemic sulfonyl ureas such as, e.g. p-toluenesulfonylbutyl urea,p-chlorobenzenesulfonyl-propyl urea and p-[2-(2-methoxy 5chlorobenzamido)-ethyl] -phenylsulfonyl-cyclohexyl urea.

For their intended use, the compounds of the invention are administeredin amounts depending on the species, the age, weight and the particularcondition of the individual being treated, and the mode ofadministration. In general, the daily dosage varies between about 0.1and 100 mg./kg. of body weight for warm-blooded animals. Suitable dosageunits, such as drages and tablets, contain preferably -200 mg. of anactive substance according to the invention, whereby the content ofactive substance is -80% by Weight. The tablets and drages are producedby combining the active substance, e.g. with solid pulverulent carrierssuch as lactose, saccharose, sorbitol or mannitol; starches such aspotato starch, maize starch or amylopectin, also laminaria powder orcitrus pulp powder; cellulose derivatives or gelatine, optionally withthe addition of lubricants such as magnesium or calcium stearate orpolyethylene glycols of suitable molecular weights. Tablets and dragecores are coated, e.g. with concentrated sugar solutions which may alsocontain, e.g. gum arabic, talcum and/or titanium dioxide, or with alacquer dissolved in readily volatile organic solvents or mixtures ofsolvents. Dyestuffs can be added to these coatings, e.g. foridentification of the various dosages of active substance.

Other suitable dosage units for oral administration are hard gelatinecapsules, as well as soft closed capsules made from gelatine and asoftener, such as glycerin. The hard capsules contain the activesubstance preferably as a granulate, e.g. in admixture with fillers suchas maize starch, and/or lubricants such as talcum or magnesium stearate,and optionally stabilizers such as sodium metabisulphite (Na S O orascorbic acid. In soft capsules, the active substance is preferablydissolved or suspended in suitable liquids such as liquid polyethyleneglycols, whereby likewise stabilizers can be added.

The following prescriptions serve to further illustrate the productionof tablets and drages:

(a) An amount of 1000 g. of1-[p-(2-butoxycarbonylaminoethyl)-phenylsulphonyl]-2-imino 3ethyl-imidazolidine is mixed with 500 g. of lactose and 270 g. of potatostarch; the m'urture is then moistened with an aqueous solution of 8.0g. of gelatine, and granulated through a sieve. After drying of thegranulate, 60.0 g. of potato starch, 60.0 g. of talcum, 10.0 ofmagnesium stearate and 20.0 g. of colloidal silicon dioxide are mixedin; the mixture is then pressed to form 10,000 tablets each weighing 200mg. and each containing mg. of active substance. Optionally, the tabletsmay be provided with grooves for a more precise adjustment of the dosageamount.

(b) A granulate is produced from 1000 g. of 1-[p-(2- butoxycarbonylaminoethyl)-phenylsulphonyl]-2-imino- 3-cyclohexyl-imidazolidine, 345.0 g. oflactose, and the aqueous solution of 6.0 g. of gelatine; the granulateis then mixed, after being dried, with 10.0 g. of colloidal silicondioxide, 40.0 g. of talcum, 40.0 g. of potato starch and 5.0 g. ofmagnesium stearate; and the mixture is pressed into 10,000 drage cores.These are subsequently coated with a concentrated syrup made from 533.0g. of crystalline saccharose, 20.0 g. of shallac, 75.0 g. of gum arabic,250 g. of talcum, 20 g. of colloidal silicon dioxide and 1.5 g. ofdystuif; and then dried. The obtained drages each weigh 240 mg. and eachcontain 100 mg. of active substance.

The following examples further illustrate the production of the newcompounds of the general Formula I and of intermediate products notdescribed hitherto; the examples in no way constitute, however, the onlyembodiments thereof. The temperatures are given in degrees centigrade.

EXAMPLE 1 From a solution of 37.0 g. of 1-[p-(2-amino-ethyl)-phenyl-sulphonyl] -2-imino-3-ethyl-imidazolidine dihydrochloride, M.P.242-244", in 50 ml. of water, the base is set free by the addition ofml. of 2 N sodium hydroxide solution and extracted three times with 100ml. each of methylene chloride. The extract which has been dried withsodium sulphate, is mixed with 11.0 g. of triethylamine and transferredto a dropping funnel which is mounted on a reaction vessel which isfitted with a stirrer and a cooling arrangement. The reaction vessel hasa second dropping funnel containing a solution of 13.7 g. of butylchloroformate in 100 ml. of methylene chloride. The two solutions arethen allowed to run into the reaction vessel in such a manner that, pertime unit, about equimolar amounts of the reactants flow into it whilethe temperature is constantly kept between 0 and 10. After completion ofthe addition, the reaction solution is stirred for one hour at roomtemperature, washed with water, dried with sodium sulphate and themethylene chloride is removed by distillation. The residual, crude1-[p[2 (butoxycarbonylamino) ethyl]phenylsulphonyl]-2-irnino-3-ethyl-imidazolidine, after recrystallizationfrom ethyl acetate, melts at 123-124".

The dihydrochlorides of1-[p-(2-amino-ethyl)-phenylsulphonyl]-2-imino-imidazolidines of generalFormula II with various substituents in the 3-position which are used inthis and the following examples as starting materials may, for example,be obtained by reaction of the appropriately substitutedZ-amino-imidazolines with p-(2- acylamido-ethyl)-benzene-sulpho-chlorides and subsequent hydrolytic cleavage of the acylradical with aqueous hydrochloric acid, as is described below forp-[2-aminoethyl)-phenylsulphonyl]-2-imino-3-butylimidazolidinedihydrochloride:

(a) 17.8 g. of 1-butyl-2-imino-imidazolidine hydrochloride areintroduced into a solution of 8.5 g. of sodium hydroxide in 85 ml. ofwater. The clear solution obtained is then treated with a solution of26.6 g. of p-(2- acetamido-ethyl)-benzene-sulphochloride in 100 ml. ofacetone, whereby heat is produced. The mixture is heated for half anhour at 90 and then evaporated in vacuum to dryness. The residual, crude1-[p-(2-acetamid0ethyl)- phenylsulphonyl]-2-imino-3-butyl-imidazolidineis recrystallized from ethyl acetate and then melts at 130-131p-(Z-acetamido-ethyl)-benzene-sulphochloride can 'be obtained asfollows:

16.3 g. of N-phenethyl-acetamido are introduced with stirring into 35.0g. of chlorosulphonic acid. The mixture obtained is stirred for 2 hoursat 60 and then poured onto ice, whereby the crudep-(2-acetamido-ethyl)-benzene-sulphochloride precipitates in crystallineform. It is removed by filtration, dried in vacuum and used directly ascrude product.

(b) A solution of 36.7 g. of 1-[p-(2-acetamidoethyl)-phenylsulphonyl]-2-imino-3-butyl-imidazolidine in 370 ml. of 2 Nhydrochloric acid is refluxed for 6 hours and then evaporated in vacuum.The residual oil is taken up in warm ethanol. On cooling, the1-[p-(2-amino-ethyl)- phenylsulphonyl]-2-imino-3-butyl-imidazolidinedihydrochloride, M.P. 231-233, crystallizes.

EXAMPLE 2 Analogously to Example 1 there are obtained: from in each case39.8 g. of 1-[p-(2-amino-ethyl)-pheny1sulphonyl]-2-imino-3-butylimidazolidine dihydrochloride, M.P. 231-233",

(21) And 10.9 g. of ethyl chloroformate,1-[p-[2-(ethoxycarbonylamino)-ethyl]-phenylsulphonyl] 2 imino-3-butyl-imidazolidine, M.P. 112-113 (from ethyl acetate).

(b) And 12.1 g. of allyl chloroformate,1-[p-[2-(allyloxycarbonylamino)-ethyl]-phenylsulphonyl] 2 imino-3-butyl-imidazolidine, M.P. 108109 (from ethyl acetate),

(c) And 13.7 g. of butyl chloroformate,l-[p-[2-butoxycarbonylamino)-ethyl]-phenylsulphonyl] 2 imino-3-butyl-imidazolidine, M.P. 114-115 (from ethyl acetate),

((1) And 13.7 g. of isobutyl chloroformate, 1-[p-[2-(isobutoxycarbonylamino) ethyl] phenylsulphonyl1-2-imino-3-butyl-imidazolidine, M.P. 137-138",

(e) And 12.3 g. of isopropyl chloroformate, 1-[p-]2-(isopropoxycarbonylamino) ethyl] phenylsulphonyl1-2-imino-3-butyl-imidazolidine, M.P. 1 15-1 16 (f) And 15.7 g. of phenylchloroformate, 1-[p-[2- (phenoxycarbonylamino) ethyl]phenylsulphonyl1-2- imin-3-butyl-imidazolidine, M.P. 145-146",

(g) And 17.1 g. of benzyl chloroformate, 1-[p-[2-(benzyloxycarbonylamino) ethyl] phenylsulfonylJ-Z-imino-3-butyl-imidazolidine, M.P. 106-108".

EXAMPLE 3 Analogously to Example 1 there are obtained: from in each case41.0 g. of 1-[p-(2-amino-ethyl)-phenylsulphonyl]-Z-imino 3cyclopentyl-imidazolidine dihydrochloride, M.P. 270 (decomposition),

(a) And 10.9 g. of ethyl chloroformate, 1-[p-[2-(ethoxycarbonylamino)ethyl] phenylsulphonyl]2-imino- 3-cyclopentyl-imidazolidine, M.P. 111-112,

(b) And 12.3 g. of isopropyl chloroformate, 1-[p-[2-(isopropoxycarbonylamino) ethyl] phenylsulphonyl1-2-imino-3-cyclopenty1-imidazolidine, M.P. 167-168 (c) And 13.7 g. ofbutyl chloroformate,1-[p-[2-(butoxycarbonylamino)-ethyl]-phenylsulphonyl] 2 imino-3-cyclopentyl-imidazolidine, M.P. 1 14-1 15 (d) And 13.7 g. of isobutylchloroformate, 1-[p-[2- (isobutoxycarbonylamino) ethyl]phenylsulphonyl1-2- imino-3-cyclopentyl-imidazolidine, M.P. 144-145 (e)And 12.1 g. of allyl chloroformate, 1-[p-[2-(allyloxycarbonylamino)ethyl] phenylsulphonyl]-2-imino- 3-cyclopentyl-imidazolidine, M.P. 113-115 EXAMPLE 4 Analogously to Example 1 there are obtained: from ineach case 42.4 g. of 1-[p-(2-amino-ethyl)-phenylsu1-phonyl]-2-imino-3-cyclohexyl-imidazolidine dihydrochloride, M.P.247-250",

(a) And 10.8 g. of ethyl chloroformate, 1-[p-[-(ethoxycarbonylamino)ethyl] phenylsulphonyl]-2-imino- 3-cyclohexyl-imidazolidine, M.P.116-117 (b) And 13.7 g. of butyl chloroformate,1-[p-[2-(butoxycarbonylamino) ethyl] phenylsulfonyl1-2-imino-3-cyclohexyl-imidazolidine, M.P. 123-124",

(c) And 15.7 g. of phenyl chloroformate, 1-[p-[2- (phenoxycarbonylamino)ethyl] phenylsulphonyl1-2- imino-3-cyclohexyl-imidazolidine, M.P.151-152".

EXAMPLE 5 Analogously to Example 1 there are obtained from in each case43.7 g. of 1-[p-(Z-amino-ethyl)-phenylsulphonyl]-2-imino 3(4-methylcyclohexyl)-imidazolidine dihydrochloride, having adecomposition point of 260,

(a) And 9.5 g. of methyl chloroformate,l-[p-[2-(methoxycarbonylamino)-ethyl]-phenylsulphonyl]-2 imino- 3-(4-methylcyclohexyl)-imidazolidine, M.P. 118-120",

(b) And 10.9 g. of ethyl chloroformate, 1-[p-[2-(ethoxycarbonylamino)ethyl] phenylsulphonyl]-2-imino- 3-(4-methylcyclohexyl)-imidazolidine,M.P. 138140.

EXAMPLE 6 Analogously to Example 1 are obtained:

(a) From 42.5 g. of 1-[p-(Z-amino-ethyl)-phenylsulphonyl] 2imino-3-(1,2-dimethyl-butyl)-imidazolidinedihydrochloride and 10.9 g. ofchloroformic acid-ethylester, 1[p-(2-(ethoxycarbonylamino)-ethyl)-phenylsulphonyl] 2 imino3-(1,2-dimethyl-butyl)imidazolidine, M.P. 75-78;

(b) From 38.1 g. of1-[p-(Z-amino-ethyl)-phenylsulphonyl]-2-imino-3-allylimidazolidine-dihydrochlorideand 10.9 g. of chloroformic acid-ethylester,l-[p-(2-(ethoxycarbonylamino)-ethyl)-phenylsulphonyl] 2imino-3-allylimidazolidine, M.P. 123-125 (c) From 42.1 g. ofl-[p-(Z-amino-ethyl)-phenylsulphonyl]2-imino-3-(3-cyclohexen-1-yl)-imidazolidine-dihydrochloride and 16.3 g.of chloroformic acid-cyclohexylester, 1[p'(2-(cyelohexyloxycarbonylamino)-ethyl)- phenylsulphonyl] 2imino-3-(3-cyclohexen-1-yl)-imidazolidine, M.P. 146-148;

(d) From 43.7 g. of 1-[p-(Z-amino-ethyl)-phenylsulphonyl] 2 imino 3cyclohexyl-4-methylimidazolidinedihydrochloride and 10.9 g. ofchloroformic acid-ethylester, 1[p-(2-etho-xycarbonylamino)-ethyl)-phenylsulphonyl] 2imino-3-cyclohexyl-4-methyl-imidazolidine, M.P. 136-138";

(e) From 43.7 g. of l-[p-(2-amino-ethyl)-phenylsulphonyl]-2-imino-3-cyclopentyl-4-ethyl-imidazolidine-dihydrochloride and 10.9 g.of chloroformic acid-ethylester, 1[p-(2-ethoxycarbonylamino)-ethyl)-phenylsulphonyl]-2-imino-3-cyclopentyl-4-ethylimidazoline, M.P. 75-77";

(f) From 43.7 g. of 1-[p-(Z-amino-propyl-phenylsulphonyl] 2imino-3-cyclohexyl-imidazoline-dihydrochlo- 7 ride and 10.9 g. ofchloroformic acid-ethylester, 1-[p-(2- (ethoxycarbonylamino)-propyl)phenylsulphonyl] 2- imino-3-cyclohexyl-imidazolidine, M.P. 100103;

(g) From 40.9 g. of l-[p-(Z-amino-ethyl)-phenylsu1-phonyl]-2-imino-3-cyclopentylimidazolidine-dihydrochloride and 13.7 g.of chloroformic acid-isobutylester, l-[p- (2- (isobutoxycarbonylamino-ethyl -phenylsulphonyl -2- imino-3-cyclopentylimidazolidine, M.P.144-145.

What is claimed is:

1. A compound of formula R2 PH R30 H -I I-omH2ms0r-N N-R,

H Y NH carbon atoms, allyl, phenyl or phenylalkyl of at most threecarbon atoms in the alkyl chain; and m is the integer 2 or 3; or thepharmaceutically acceptable acid addition salts thereof.

2. A compound according to claim 1, which is 1- [p-[2-ethoxycarbonylamino)-ethyl]-pheny1su1fonyl] 2-imino-3-cyclohexyl-imidazolidine.

3. A compound according to claim 1, which is 1-[p-[2-(ethoxycarbonylamino)-ethyl]-phenylsulfonyl] Z-imino-3-cyclopentyl-imidazolidine.

References Cited UNITED STATES PATENTS 3,538,085 11/1970 Dietrich260309.7

OTHER REFERENCES Dietrich et al.: Chem. Abst., vol. 72, No. 12725q(1970).

NATALIE TROUSOF, Primary Examiner US. Cl. X.R.

260-463, 543 R, 545 R, 556 AR; 424-273

